Propionic acid derivatives

Propionic acid, CHgCHgCOOH, resembles acetic acid in its chemical properties. Propionyl Co A is an activated compound (C 1.2) and may be substituted easily at the carbonyl C-atom by nucleophibc groups and at the x-carbon atom by electrophilic groupings. 

Secondary products are formed with the participation of propionyl CoA in microorganisms and animals. 

Biosynthesis Qnd Degradation of Propionic Acid Propionyl CoA may be built 

Propionyl CoA is carboxylated by a biotin-containing enzyme (C 3.1) to methylmalonyl CoA. Propionic acid is derived from propionyl CoA by transfer of the CoA residue or by hydrolysis. It is degraded via acrylic acid and lactic acid to pyruvic acid (Fig. 83). 

1 (R)-Methylmalonyl CoA mutase (coenzyme Bi2 d P dent), methylmalonyl CoA racemase  

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An isoindol1 none moiety forms part of the aromatic moiety of yet another antiinflammatory propionic acid derivative. Carboxylation of the anion from -nitro-ethylbenzene (45) leads directly to the propionic acid (46). Reduction of the nitro group followed by condensation of the resulting aniline (47) with phthalic anhydride affords the corresponding phthalimide (48). Treatment of that intermediate with zinc in acetic acid interestingly results in reduction of only one of the carbonyl groups to afford the isoindolone. There is thus obtained indoprofen (49). ... 

Propiolactone is subject to attack by enolate ions to give propionic acid derivatives of ketones. It may likewise react with nucleophilic enamines to give carboxyethylation according to the reactions. The morpholide is easily hydrolyzed to the corresponding acid. 

On the other hand, the method of Mukaiyama can be succesfully applied to silyl enol ethers of acetic and propionic acid derivatives. For example, perfect stereochemical control is attained in the reaction of silyl enol ether of 5-ethyl propanethioate with several aldehydes including aromatic, aliphatic and a,j5-unsaturated aldehydes, with syir.anti ratios of 100 0 and an ee >98%, provided that a polar solvent, such as propionitrile, and the "slow addition procedure " are used. Thus, a typical experimental procedure is as follows [32e] to a solution of tin(II) triflate (0.08 mmol, 20 mol%) in propionitrile (1 ml) was added (5)-l-methyl-2-[(iV-l-naphthylamino)methyl]pyrrolidine (97b. 0.088 mmol) in propionitrile (1 ml). The mixture was cooled at -78 °C, then a mixture of silyl enol ether of 5-ethyl propanethioate (99, 0.44 mmol) and an aldehyde (0.4 mmol) was slowly added to this solution over a period of 3 h, and the mixture stirred for a further 2 h. After work-up the aldol adduct was isolated as the corresponding trimethylsilyl ether. Most probably the catalytic cycle is that shown in Scheme 9.30. 

For therapeutical purposes, a likewise frequently used group of drug compounds are the nonsteroidal anti-inflammatory drugs (NSAID). Among the best known representatives of the aryl acetic acid derivatives is diclofenac as well as ibuprofen, an aryl propionic acid derivative. As both have acidic properties, they dissociate while being dissolved and may form salts with amphiphilic properties. Together with appropriate counterions these amphiphilic organic acids may form lyotropic mesophases with water even at room or body temperature, for example, diclofenac diethylamine... 

Indometacin is an indole acetic acid derivative, while naproxen is a propionic acid derivative. Both are non-steroidal anti-inflammatory drugs (NSAIDs). Indometacin is associated with a higher incidence of side-effects, particularly gastrointestinal as well as headache and dizziness. 

Naproxen is a non-steroidal anti-inflammatory agent classified as a propionic acid derivative. 

The development of enantioselective aldol reactions has been widely studied in conjunction with the synthesis of natural products. Highly enantioselective aldol reactions have been achieved by employing chiral enolates of ethyl ketones and propionic acid derivatives.(1) On the other hand, achieving high asymmetric induction in the asymmetric aldol reaction of methyl ketones is still a problem.(2)... 

A biaryl propionic acid derivative containing a furan ring as a prominent feature has antiinflammatory activity. The patented synthesis involves a straightforward organometallic addition of ethyl lithioacetate to aldehyde 12 followed by saponification... 

This series of anti-inflammatory, analgesic, and fever-reducing compounds (ibuprofen, naproxene, ketoprofen, fenprofen) can be equally identified as both propionic acid derivatives as well as phenylpropionic acid derivatives. The mechanism of their action is not conclusively known however, it has been suggested that it is also connected with the suppression of prostaglandin synthetase activity. 

Apart from the salicylates NSAIDs include several classes of weak acids like propionic acid derivatives such as ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen. Phenylbutazone is the most important representative of the pyrazolon derivatives which have a bad reputation for their risk of potentially fatal bone-marrow toxicity. To the acetic acid derivatives belong in-domethacin, diclofenac and sulindac. Sulindac is a pro-drug with less toxicity than indomethacin. The enolic acids include piroxicam, droxicam and tenoxicam. Meloxicam is an analog of piroxicam and has a high selectivity for COX-2. 

Ibuprofen (Advil), flurbiprofen (Ansaid), fenoprofen (Naifon), ketoprofen (Orudis), and naproxen (Naprosyn) are all 2-substituted propionic acid derivatives. They block the production of prostaglandins via inhibition of COX and therefore are similar to the salicylates in that... 

Oxaprozin (Daypro) has pharmacological properties that are similar to those of other propionic acid derivatives. However, it has a very long half-life (more than 40 hours) and therefore can be effective with once-a-day treatment. 

Brand Name(s) Oruvail OTC Actron, Orudis KT Chemical Class Propionic acid derivative... 

Flurbiprofen is a propionic acid derivative with a possibly more complex mechanism of action than other NSAIDs. Its (S)( ) enantiomer inhibits COX nonselectively, but it has been shown in rat tissue to also affect tumor necrosis factor- (TNF- ) and nitric oxide synthesis. Flepatic metabolism is extensive its (R) +) and (S) ) enantiomers are metabolized differently, and it does not undergo chiral conversion. It does demonstrate enterohepatic circulation. 

Ketoprofen is a propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase. Its pharmacokinetic characteristics are given in Table 36-1. Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life. 

Oxaprozin is another propionic acid derivative NSAID. As noted in Table 36-1, its major difference from the other members of this subgroup is a very long half-life (50-60 hours), although oxaprozin does not undergo enterohepatic circulation. It is mildly uricosuric, making it potentially more useful in gout than some other NSAIDs. The drug has the same benefits and risks that are associated with other NSAIDs. 

An early effort to generate a 3-lithiated propionic acid derivative and react it with (external) electrophiles was reported in 1978 [42]. Since simple 3-lithioesters failed to undergo the required reaction, the alkyl carboxylate portion was protected by preceding conversion to the carboxylate anion. Treatment of lithium 3-bromo-propionate with lithium naphthalide generated the desired dilithiated propionic acid, which gave moderate yields of y-hydroxy acid addition products with carbonyl compounds, Eq. (45). 

Similarly, CrL has also been employed in the resolution of a range of 2-substi-tuted propionic acid derivatives (Figure 10.12) in ionic liquids [62]. 

The resin-bound phenylene diamine intermediates 3 are then generated by nitro group reduction with tin(II) chloride in NMP and cyclization/ aromatization with a wide variety of aldehydes gave the resin-bound benzimidazole intermediates 4. The treatment of this intermediate with 50% TFA/DCM liberates the substituted 3-(benzoimidazol-l-yl)-propionic acid derivative 4a. Analysis of this intermediate by HPLC and LC-MS gave a measure of the purity of the resin-bound product and enabled the optimization of conditions for the incorporation of the Rl-nitroarenes and R2-aldehydes by an iterative process. 

Reaction of 2-aminopyridines with acrylic acid or methacrylic acid in boiling water for 2-20 hours gave betaine hydrates 262 (R3 = H) in 11-88% yields (Scheme 20) (92KGS80). When 2-aminopyridine reacted with methyl metharylate in acetic acid for 24 hours or 2-aminopyridine and its 5-bromo and 5-chloro derivatives reacted with acrylic acid in boiling toluene for 24 hours or 2-aminopyridine reacted with crotonic acid in boiling toluene for 20 hours, 3-(2-pyridylamino)propionic acid derivatives 263 were the products. When 5-chloro-2-aminopyridine reacted with acrylic... 

Vargas F, Rivas C, Miranda MA, Bosca F. Photochemistry of the nonsteroidal anti-inflammatory dmgs, propionic acid derived. Pharmazie 1991 46 ... 

Naito, Y., Y. Yamaura, Y. Inoue, C. Fukaya, K. Yokoyama, Y. Nakagawa, and T. Fujita. 1992. Quantitative structure-activity relationships of 2-[4-(thiazol-2-yl)phenyl]propionic acids derivatives inhibiting cyclooxygenase. Eur. J. Med. Chem. 27, 645-654. (Abnormality of back calculation from log P of protonated base confirmed by T. Fujita, private communication.)... 

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